ABSTRACT The objective of this research is to develop and validate novel ultrasound-based methods for the detection and localization of pulmonary nodules (PNs) during minimally invasive thoracic surgery - Video Assisted Thoracic Surgery (VATS), and robotic surgery. Lung cancer is the leading cause of cancer deaths in the U.S., with over 220,000 new cases diagnosed each year. PNs are detected by Computerized Tomographic (CT) scanning. VATS and robotic surgery are performed to resect a PN, for diagnosis and therapeutic purposes. However, during the surgery, PNs can be extremely difficult to locate precisely. Small nodules are particularly difficult to feel. Therefore, there is no guarantee that the nodule will be in the resected region of the lung parenchyma. This results in positive margins and sometimes a complete miss of the tumor in the resected lung wedge. Ultrasound is used as an imaging modality based on the ability to create an image because the sound waves bounce back, often in a straight line. Ultrasound can reliably demonstrate gallstones, estimate the size of abdominal aneurysms, and can visualize blood moving through cardiac chambers, the basis of echocardiography. Exposure of lung tissue to ultrasound waves results in multiple scattering due to thousands of air/liquid interfaces from air-filled alveoli and alveolar walls. The objective of this research is to develop novel ultrasound sequences, specific to the lung, exploiting the very complex properties of ultrasound multiple scattering in the lung parenchyma. Our approach is based on the following paradigm: Because PNs are not filled with alveoli, they will not be responsible for as much multiple scattering as the normal parenchymal lung tissue. We propose that mapping the amount of multiple scattering in lung parenchyma will enable us to map and accurately localize PNs in real time. We will accomplish two aims. Specific Aim 1: To develop methods to exploit multiple scattering of ultrasound waves applied to lung tissue to determine the location of PNs. We will develop ultrasound sequences and signal processing methods to quantify the amount of multiple scattering locally. Specific Aim 2: To image pulmonary nodules to facilitate accurate excision using ultrasound. Simulated PNs will be excised using surgical staplers under ultrasound guidance to localize the PNs, create images by mapping the multiple scattering patterns and image the staplers in relation to the simulated PNs. In the future, the developed sequences will be implemented on an intravascular ultrasound probe placed through a flexible bronchoscope into the pleural space, which will be used during minimally invasive surgery to locate and ensure proper resection of PNs. This should reduce the duration and enhance the safety of the procedure. The ultrasound signals will demonstrate the PN and its location relative to the closed stapler, reducing the incidence of positive resection margins. This innovative new use for ultrasound will increase safety and improve outcomes of VATS and robotic resection of malignant primary and metastatic PNs.